There are two major types of skin cancer, non-melanoma skin cancer (NMSC) and melanoma. NMSC includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Together, new cases of BCC and SCC are diagnosed in more than 2 million individuals each year. Skin cancer is most commonly caused by excessive sun exposure and occupational chemical exposure. Individuals who are at increased risk of developing NMSC include the elderly, outdoor workers, outdoor sport enthusiast and organ transplant recipients. NMSC is also important due to its financial impact on our heath care system with a calculated direct cost of 1.4 billion dollars in 2004.
Nonmelanoma skin cancer is the most prevalent cancer in the United States with ˜1.25 million new cases diagnosed each year. Excessive exposure to solar radiation is a common cause of NMSC. These tumors, which arise from basal and squamous keratinocytes, comprise the most common cancer in the United States and are nearly equivalent in incidence to all other forms of cancer combined. NMSC is typically treated with topical 5-fluorouracil (5FU) and/or by surgical excision. Although these techniques can be effective for eliminating skin cancer they can also produce significant damage to the surrounding non-tumor cells. As such, novel treatments and improved prevention strategies are clearly needed to address this issue. Recently, there has been a great deal of interest in determining if cannabinoids (CBs) can be developed as chemotherapeutic agents for NMSC by identifying molecular pathways targeted by these compounds. CBs are signaling lipids that are involved in processes such as pain, inflammation, appetite control, learning/memory, and drug addiction. The prototypic exogenous CB, Δ9-tetrahydrocannabinol (Δ9-THC), is the active component in marijuana. Arachidonyl ethanolamide (AEA) or anandamide is the prototypic endogenous CB (endocannabinoid) and its effects mimic those of Δ9-THC. Since the identification of AEA, other endocannabinoids have been identified including 2-arachidonoyl glycerol (2-AG), oleoyl ethanolamide (OEA), and the anti-inflammatory lipid, palmitoyl ethanolamide (PEA). Exogenous and endogenous CBs elicit biological responses by binding to and activating CB receptors 1 and 2 (CB1 and CB2) or the vanilloid receptor (VR1). CBs are then transported into cells via the anandamide membrane transporter (AMT) and its action terminated by amidases including fatty acid amide hydrolase (FAAH) or monoacylglyceride lipase (MAGL).
The utility of CBs in tumor prevention was first recognized where oral administration of Δ9-THC was shown to reduce Lewis lung adenocarcinoma growth. The endocannabinoid-induced reduction in tumor growth shown may be mediated by components of the CB system. For example, epidermal tumor growth was blocked by the synthetic CB1/CB2 receptor agonist, WIN-55, 212-2. The VR1 receptor was shown to be critical for endocannabinoid induction of cell death via a Ca2+ sensitive mechanism. Cellular FAAH levels are also an important determinant of endocannabinoid-induced cell death at least because overexpression of FAAH protected cells from AEA-mediated cell death while genetic deletion of FAAH increased their susceptibility to cell killing. Thus, it appears that cellular proteins capable of modulating endocannabinoid action play a role in its ability to induce cell death.
Another cellular protein that is indicated to be involved in endocannabinoid-induced cell death is cyclooxygenase-2 (COX-2). COX-2 expression, as well as PG levels, is commonly elevated in NMSC and other epithelial tumors. COX-2 metabolizes arachidonic acid to prostaglandins, which promote growth and survival of tumor cells. These prostaglandins include E-, F-, D- and J-type prostaglandins. COX-2 also metabolizes endocannabinoids to form prostaglandin-ethanolamides (PG-EA). COX-2 metabolizes AEA to ethanolamide conjugated prostaglandins E, F, and D. However, J-series PG-ethanolamides have never been described previously.
AEA has been shown to induce cell death in the COX-2 overexpressing squamous carcinoma cell line JWF2. In contrast, AEA does not induce cell death in HaCaT keratinocytes, which express low basal levels of COX-2. Resistance to AEA-mediated cell death in HaCaT cells was reversed by overexpressing COX-2 in these cells. Prostaglandins have been identified to be involved in AEA-mediated cell death. D-type prostaglandins were predominantly formed in AEA-exposed JWF2 cells although significant increases in E- and F-type prostaglandins were also seen. Cells treated with various prostaglandins or PG-EA to examine AEA-induced cell death indicated that PGD2 and PGD2-EA are cytotoxic to JWF2 keratinocytes and that PGD2 dehydration products, PGJ2 and 15-deoxy Δ12,14 PGJ2, were also inducers of cell death.